EP0964855A1 - Process for preparing substituted pyrimidine derivatives - Google Patents

Process for preparing substituted pyrimidine derivatives

Info

Publication number
EP0964855A1
EP0964855A1 EP98901950A EP98901950A EP0964855A1 EP 0964855 A1 EP0964855 A1 EP 0964855A1 EP 98901950 A EP98901950 A EP 98901950A EP 98901950 A EP98901950 A EP 98901950A EP 0964855 A1 EP0964855 A1 EP 0964855A1
Authority
EP
European Patent Office
Prior art keywords
general formula
azaprop
dimethylamino
ylidene
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP98901950A
Other languages
German (de)
French (fr)
Other versions
EP0964855B1 (en
Inventor
Beat Schmidt
Gerhard Stucky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lonza AG
Original Assignee
Lonza AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lonza AG filed Critical Lonza AG
Publication of EP0964855A1 publication Critical patent/EP0964855A1/en
Application granted granted Critical
Publication of EP0964855B1 publication Critical patent/EP0964855B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C07D239/40—One sulfur atom as doubly bound sulfur atom or as unsubstituted mercapto radical

Definitions

  • the invention includes a new access to substituted Pvnmidin ⁇ em aten of alicemeine formula
  • T ⁇ azin z B is also known ester in a ⁇ .usbe ⁇ te of 42% to 4-Hvdroxypy ⁇ m ⁇ dm-5-carbonsaureethvlester CHuffmann et al J örg Chem 1962, 27, 551-558)
  • Y has the meaning of an oxygen atom or a
  • R stands for cyano or for a group
  • R for optionally substituted alkyl, alkoxy, hydroxy, amino, alkylamino
  • Dialkylamino, phenyl or benzyl means.
  • Alkyl has the meaning of C, _ 6 - alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl and its isomers or hexyl and its
  • Isomers preferably of C alkyl.
  • the alkyl radicals of alkoxy, alkylamino or dialkylamino are also included in this meaning of alkyl.
  • the radicals mentioned can also be mono- or polysubstituted with, for.
  • Halogen is usually fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
  • X represents a halogen atom.
  • This compound is known in the form of its chloride as "Gold's reagent". The preparation of the gold reagent in a known manner by the reaction of cyanuric chloride with N, N-dimethylformamide ACCORDANCE H. Gold, Angew. Chem. 1960, 72, 956- 959.
  • the gold reagent or another halide of the general formula II can be made available in situ and without isolating it for the subsequent stage.
  • Preferred [3- (dimethylamino) -2-azaprop-2-en-1-ylidene] dimethylammonium halide of the general formula II is the “gold reagent” or the [3- (dimethylamino) -2-azaprop-2-ene -l-ylidene] dimethylammonium chloride.
  • Suitable compounds of the general formula III are the substituted acetamides in which Y has the meaning of oxygen and R has the meaning of
  • malonic acid diamide or the malonic acid 6 -alkyl ester monoamides in particular malonic acid
  • cyanoacetamide and the 2-cyano-thioacetamide with the meaning of R being cyano and Y being oxygen or sulfur.
  • the gold reagent or another halide of the general formula II can generally be used stoichiometrically, but preferably in a slight excess, for the compound of the general formula III.
  • the reaction takes place in the presence of a base.
  • a conventional alkali alcoholate such as, for. B. Na, or K-methylate, ethylate or tert-butoxide used.
  • the reaction expediently proceeds in the presence of an organic solvent such as, for. As dimethoxyethane, dioxane, tetrahydrofuran or methanol.
  • the reaction temperature is usually chosen in the range between 20 ° C and 100 ° C. It is preferred to work at the reflux temperature.
  • the resulting pyrimidine of the general formula I can in a simple manner, usually by filtration, the
  • the substituted pyrimidine derivatives of the general formula I can be obtained in good yields of over 80%.
  • Cyanuric chloride (46.67 g, 0.252 mol) was tert with N, N-dimethylformamide (121.33 g, 1.66 mol) in 250 ml. Butyl methyl ether heated for 30 to 40 min. An exothermic reaction then occurred and CO 2 gas was released over a period of 1 to 2 hours.
  • reaction mixture was boiled overnight. After cooling the reaction mixture, the title product is obtained by rapid filtration under an N 2 atmosphere and washing with tert. Isolate butyl methyl ether. After drying in a desiccator, the title product was isolated in a yield of 112.15 g (90.7%) in the form of a slightly yellow solid.
  • Methyl oxalate (0.2 eq.) And monomethyl malonate (58.55 g, 0.50 mol) were added to the initially introduced sodium methylate (279.4 g, 1.5 mol, 29% in methanol). 350 ml of dimethoxyethane were added. Then the solid gold reagent (89.35 g, 0.55 mol) prepared according to Example 1 was added in spatulas. The suspension was stirred for 18 hours at room temperature. The yellow suspension was poured onto an aqueous, ice-cold hydrochloric acid solution (2 eq. HC1).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

PCT No. PCT/EP98/00074 Sec. 371 Date Dec. 17, 1999 Sec. 102(e) Date Dec. 17, 1999 PCT Filed Jan. 8, 1998 PCT Pub. No. WO98/30549 PCT Pub. Date Jul. 16, 1998A process for preparing substituted pyrimidine derivatives of the general formula (I): in which a [3-(dimethylamino)-2-azaprop-2-en-1-ylidine]dimethylammonium halide is reacted with a substituted acetamide. The compounds of general formula (I) are important intermediate products for pharmaceutical or agrochemical active substances.

Description

v erjähren zur Herstellung von substituierten P\ πmidindem atenage for the production of substituted P \ πmidindem aten
Die Erfindung beinhaltet einen neuen Zugang zu substituierten Pvnmidinαem aten der alicemeinen FormelThe invention includes a new access to substituted Pvnmidinαem aten of alicemeine formula
woπn "V und R die nachstehend erläuterten Bedeutungen haben Die genannten Verbindungen haben em sehr breites Anwendungsspektrum z B als Zwischenprodukte für pnarmazeutische oder agrochemische Wirkstoffewoπn "V and R have the meanings explained below. The compounds mentioned have a very wide range of applications, for example as intermediates for pharmaceutical or agrochemical active substances
Bekannt ist Verbindungen der allgemeinen Formel I durch Umsetzung von Tπs- formammo-methan mit CH-aciden Carbonsaureamiden zu erhalten (Brederbeck et al.It is known to obtain compounds of the general formula I by reacting Tπs-formammomethane with CH-acidic carboxamides (Brederbeck et al.
Chem Ber 1965, 98, 3883-3887) Beispielhaft erwähnt wird die Umsetzung vonTπs- formammo-methan mit Malonsaureethylesteramid m einer Ausbeute von 1 1% zum entsprechenden 4-Hydroxypyπmιdm-5 -carbonsaureethvlester (4-H vdroxy-5- ethoxycarbonylpyπmidin)Chem Ber 1965, 98, 3883-3887) The reaction of Tπs-formammomethane with malonic acid ethyl ester amide in a yield of 1% to the corresponding 4-hydroxypyπmιdm-5-carboxylic acid ethyl ester (4-H vdroxy-5-ethoxycarbonylpyπmidin) is mentioned as an example.
Ausserdem bekannt ist die Umsetzung von Tπazin z B mit lester in einer Λ.usbeιte von 42% zum 4-Hvdroxypyπmιdm-5-carbonsaureethvlester CHuffmann et al J örg Chem 1962, 27, 551-558)The implementation of Tπazin z B is also known ester in a Λ.usbeιte of 42% to 4-Hvdroxypyπmιdm-5-carbonsaureethvlester CHuffmann et al J örg Chem 1962, 27, 551-558)
Diese Synthesen beinhalten den Nachteil, dass sie einerseits relativ schlechte Ausbeiten liefern, anderseits von schwer zuganglichen und relativ teuren Ausgangsverbindungen ausgehen und somit nicht wirtschaftlich sindThese syntheses have the disadvantage that, on the one hand, they produce relatively poor workouts, on the other hand, they are based on starting compounds which are difficult to access and relatively expensive and are therefore not economical
Die Aufgabe der Erfindung bestand folglich dann emen neuen irtschaftlichen Zugang zu den Verbindungen der allgemeinen Formel I zu entwickeln, die die genannten Nachteile nicht emschhesstThe object of the invention was therefore to develop a new economic approach to the compounds of the general formula I which does not suffer from the disadvantages mentioned
Die Aufgabe konnte gelost werden mit dem erfmdungsgemassen Verfahren nach Anspruch 1 oder 5 In der allgemeinen Formel I hat Y die Bedeutung von einem Sauerstoffatom oder einemThe task could be solved with the inventive method according to claim 1 or 5 In the general formula I, Y has the meaning of an oxygen atom or a
Schwefelatom.Sulfur atom.
R steht flir Cyano oder flir eine GruppeR stands for cyano or for a group
worin R flir gegebenenfalls substituiertes Alkyl, Alkoxy, Hydroxy, A ino, Alkylamino,wherein R for optionally substituted alkyl, alkoxy, hydroxy, amino, alkylamino,
Dialkylamino, Phenyl oder Benzyl bedeutet.Dialkylamino, phenyl or benzyl means.
Alkyl hat zweckmässig die Bedeutung von C,_6- Alkyl-, wie Methyl, Ethyl, n-Propyl, iso- Propyl, n-Butyl, sec-Butyl, tert-Butyl, Pentyl und seine Isomeren oder Hexyl und seineAlkyl has the meaning of C, _ 6 - alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl and its isomers or hexyl and its
Isomeren, vorzugsweise von C - Alkyl. In dieser Bedeutung von Alkyl mitumfasst sind die Alkylreste von Alkoxy, Alkylamino oder Dialkylamino. Die genannten Reste können zudem ein- oder mehrfach substituiert sein mit z. B. Alkyl, Alkoxy, Amino oder Halogen.Isomers, preferably of C alkyl. The alkyl radicals of alkoxy, alkylamino or dialkylamino are also included in this meaning of alkyl. The radicals mentioned can also be mono- or polysubstituted with, for. As alkyl, alkoxy, amino or halogen.
Halogen steht üblicherweise für Fluor, Chlor, Brom oder Jod, bevorzugt für Chlor oder Brom.Halogen is usually fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
Ausgangsprodukt des erfmdungsgemassen Verfahrens gemass der Variante nach AnspruchStarting product of the inventive method according to the variant according to claim
1 ist das [3-(Dimethylamino)-2-azaprop-2-en-l-yliden] dimethylammonium halogenid der allgemeinen Formel1 is the [3- (dimethylamino) -2-azaprop-2-en-l-ylidene] dimethylammonium halide of the general formula
XX
worin X ein Halogenatom bedeutet. Diese Verbindung ist in Form seines Chlorids als „Gold-Reagenz" bekannt. Die Herstellung des Gold-Reagenz erfolgt auf bekannte Weise durch Umsetzung von Cyanurchlorid mit N.N-Dimethylformamid gemass H. Gold, Angew. Chem. 1960, 72, 956-959.wherein X represents a halogen atom. This compound is known in the form of its chloride as "Gold's reagent". The preparation of the gold reagent in a known manner by the reaction of cyanuric chloride with N, N-dimethylformamide ACCORDANCE H. Gold, Angew. Chem. 1960, 72, 956- 959.
Alternativ kann gemass Anspruch 5 das Gold-Reagenz bzw. ein anders Halogenid der allgemeinen Formel II in situ und ohne es zu isolieren für die Folgestufe zur Verfügung gestellt werden. Bevorzugtes [3-(Dimethylamino)-2-azaprop-2-en-l-yliden] dimethylammonium halogenid der allgemeinen Formel II ist das „Gold-Reagenz" bzw. das [3-(Dimethylamino)-2- azaprop-2-en-l-yliden] dimethylammonium chlorid.Alternatively, according to claim 5, the gold reagent or another halide of the general formula II can be made available in situ and without isolating it for the subsequent stage. Preferred [3- (dimethylamino) -2-azaprop-2-en-1-ylidene] dimethylammonium halide of the general formula II is the “gold reagent” or the [3- (dimethylamino) -2-azaprop-2-ene -l-ylidene] dimethylammonium chloride.
Die erfindungsgemässe Umsetzung mit der Verbindung der allgemeinen Formel II erfolgt mit einer Verbindung der allgemeinen FormelThe reaction according to the invention with the compound of the general formula II takes place with a compound of the general formula
YY
H2N Λ^R πiH 2 N Λ ^ R πi
worin Y und R die genannte Bedeutung hat.where Y and R have the meaning given.
Geeignete Verbindungen der allgemeinen Formel III sind die substituierten Acetamide worin Y die Bedeutung hat von Sauerstoff und R die Bedeutung hat vonSuitable compounds of the general formula III are the substituted acetamides in which Y has the meaning of oxygen and R has the meaning of
Besonders bevorzugt sind folglich Malonsäurediamid oder die Malonsäure-Cι_6- alkylestermonoamide, insbesondere die Malonsäure Consequently, particular preference is given to malonic acid diamide or the malonic acid 6 -alkyl ester monoamides, in particular malonic acid
Ebenfalls geeignete Verbindungen der allgemeinen Formel III sind das Cyanacetamid und das 2-Cyan-thioacetamid mit der Bedeutung von R gleich Cyano und Y Sauerstoff bzw. Schwefel.Also suitable compounds of the general formula III are the cyanoacetamide and the 2-cyano-thioacetamide with the meaning of R being cyano and Y being oxygen or sulfur.
Das Gold-Reagenz bzw. ein anderes Halogenid der allgemeinen Formel II kann in der Regel stöchiometrisch, bevorzugt aber in einem leichten Überschuss zur Verbindung der allgemeinen Formel III eingesetzt werden.The gold reagent or another halide of the general formula II can generally be used stoichiometrically, but preferably in a slight excess, for the compound of the general formula III.
Die Umsetzung verläuft in Gegenwart einer Base.The reaction takes place in the presence of a base.
Bevorzugt wird ein übliches Alkalialkoholat wie z. B. Na-, oder K-methylat,-ethylat oder tert-butylat eingesetzt. Zweckmässig verläuft die Reaktion in Gegenwart eines organischen Lösungsmittels wie z. B. Dimethoxyethan, Dioxan, Tetrahydrofuran oder Methanol.A conventional alkali alcoholate such as, for. B. Na, or K-methylate, ethylate or tert-butoxide used. The reaction expediently proceeds in the presence of an organic solvent such as, for. As dimethoxyethane, dioxane, tetrahydrofuran or methanol.
Die Reaktionstemperatur wählt man üblicherweise im Bereich zwischen 20°C und 100°C Bevorzugt wird bei Rückflusstemperatur gearbeitet.The reaction temperature is usually chosen in the range between 20 ° C and 100 ° C. It is preferred to work at the reflux temperature.
Nach einer Reaktionszeit von 1 h bis 20 h kann das resultierende Pyrimidin der allgemeinen Formel I auf einfache Weise, in der Regel durch Filtration, demAfter a reaction time of 1 h to 20 h, the resulting pyrimidine of the general formula I can in a simple manner, usually by filtration, the
Reaktionsgemisch entnommen werden. In dem Fall wo im resultierenden Pyrimidin der allgemeinen Formel I R die Bedeutung einer Esterfunktion hat, kann durch saure oder basische Aufarbeitung auf einfache Weise die entsprechende Pyrimidincarbonsäure erhalten werden.Reaction mixture are removed. In the case where the resulting pyrimidine of the general formula I R has the meaning of an ester function, the corresponding pyrimidinecarboxylic acid can be obtained in a simple manner by acidic or basic workup.
Mit dem erfindungsgemässen Verfahren lassen sich die substituierten Pyrimidinderivaten der allgemeinen Formel I in guten Ausbeuten von über 80% gewinnen. With the process according to the invention, the substituted pyrimidine derivatives of the general formula I can be obtained in good yields of over 80%.
33
Beispiele:Examples:
Beispiel 1 Verfahren zur Herstellung von [3-(DimethyIamino)-2-azaprop-2-en-l-yliden] dimethylammonium chlorid (Gold-Reagenz)Example 1 Process for the preparation of [3- (DimethyIamino) -2-azaprop-2-en-l-ylidene] dimethylammonium chloride (gold reagent)
Cyanurchlorid (46,67 g, 0,252 mol) wurde mit N,N-Dimethylformamid (121,33 g, 1,66 mol) in 250 ml tert. Butylmethylether während 30 bis 40 min erhitzt. Danach trat eine exotherme Reaktion auf, und während 1 bis 2 Stunden wurde CO2-Gas frei. DasCyanuric chloride (46.67 g, 0.252 mol) was tert with N, N-dimethylformamide (121.33 g, 1.66 mol) in 250 ml. Butyl methyl ether heated for 30 to 40 min. An exothermic reaction then occurred and CO 2 gas was released over a period of 1 to 2 hours. The
Reaktionsgemisch wurde über Nacht gekocht. Nach Abkühlen des Reaktionsgemisches Hess sich das Titelprodukt durch rasche Filtration unter N2-Atmosphäre und Waschen mit tert. Butylmethylether isolieren. Nach Trocknen im Exsikkator isolierte man das Titelprodukt in einer Ausbeute von 112,15 g (90,7%) in Form eines leicht gelben Feststoffes.The reaction mixture was boiled overnight. After cooling the reaction mixture, the title product is obtained by rapid filtration under an N 2 atmosphere and washing with tert. Isolate butyl methyl ether. After drying in a desiccator, the title product was isolated in a yield of 112.15 g (90.7%) in the form of a slightly yellow solid.
Fp = 103 °CMp = 103 ° C
Η NMR (DMSOd6, 400 MHz) δ = 3,2 (s,-6H);Η NMR (DMSO d6 , 400 MHz) δ = 3.2 (s, -6H);
3,27 (s, 6H); 8,62 (s, 2H).3.27 (s, 6H); 8.62 (s, 2H).
Beispiel 2aExample 2a
Verfahren zur Herstellung von 4-Hydroxypyrimidin-5-carbonsäuremethylesterProcess for the preparation of 4-hydroxypyrimidine-5-carboxylic acid methyl ester
Zum vorgelegten Natriummethylat (279,4 g, 1,5 mol, 29% in Methanol) gab man Oxalsäuremethylester (0,2 eq.) und Malonsäuremonomethylestermonoamid (58,55 g, 0,50 mol). Man fügte 350 ml Dimethoxyethan zu. Dann gab man das feste, gemass Beispiel 1 hergestellte Goldreagenz (89,35 g, 0,55 mol) spatelweise zu. Man Hess die Suspension während 18 Stunden bei Raumtemeperatur rühren. Die gelbe Suspension wurde auf eine wässrige, eiskalte Salzsäurelösung (2 eq. HC1) gegossen. Nach Filtration bei pH 9-10 wurde das feuchte Natriumsalz des Titelproduktes in HCl-gesättigtem Methanol aufgenommen, 15 min gerührt, filtriert und getrocknet. Die Ausbeute des Titelproduktes in Form seines Hydrochlorids betrug 52,3 g (55%). Η NMR (DMSOd6, 400 MHz) δ 3,8 (s, 3H);Methyl oxalate (0.2 eq.) And monomethyl malonate (58.55 g, 0.50 mol) were added to the initially introduced sodium methylate (279.4 g, 1.5 mol, 29% in methanol). 350 ml of dimethoxyethane were added. Then the solid gold reagent (89.35 g, 0.55 mol) prepared according to Example 1 was added in spatulas. The suspension was stirred for 18 hours at room temperature. The yellow suspension was poured onto an aqueous, ice-cold hydrochloric acid solution (2 eq. HC1). After filtration at pH 9-10, the moist sodium salt of the title product was taken up in HCl-saturated methanol, stirred for 15 min, filtered and dried. The yield of the title product in the form of its hydrochloride was 52.3 g (55%). Η NMR (DMSO d6 , 400 MHz) δ 3.8 (s, 3H);
5,7 - 6,4 (breit, 1H);5.7 - 6.4 (broad, 1H);
8.4 (s, 1H);8.4 (s, 1H);
8.5 (s, 1H).8.5 (s, 1H).
Beispiel 2bExample 2b
Verfahren zur Herstellung von 4-Hydroxypyrimidin-5-carbonsäure Das gemass Beispiel 2a) erhaltene feuchte Natriumsalz des 4-Hydroxypyrimidin-5- carbonsäuremethylesters wurde in Wasser/Tetrahydrofuran = 1 : 1 aufgenommen und 1,0 eq LiOH.H2O zugefügt. Nach Hydrolyse des Esters über 3,5 Stunden bei 0 °C und 2 Stunden bei Raumtemperatur wurde das Tetrahydrofuran weitgehend eingedampft und bei 0 °C mit aq. HCl-Lösung ein pH von 3 eingestellt. Nach ca. 45 Minuten bei 0 °C wurde das Titelprodukt ab filtriert. Nach Trocknen wurde die Säure in einer Ausbeute von 3,55 g (78%) erhalten.Process for the preparation of 4-hydroxypyrimidine-5-carboxylic acid The moist sodium salt of the 4-hydroxypyrimidine-5-carboxylic acid methyl ester obtained according to Example 2a) was taken up in water / tetrahydrofuran = 1: 1 and 1.0 eq LiOH.H 2 O was added. After hydrolysis of the ester over 3.5 hours at 0 ° C. and 2 hours at room temperature, the tetrahydrofuran was largely evaporated and a pH of 3 was set at 0 ° C. with aq. HCl solution. After about 45 minutes at 0 ° C, the title product was filtered off. After drying, the acid was obtained in a yield of 3.55 g (78%).
Η NMR (DMSOd6, 400 MHz) δ 8.6 (s, 1H);Η NMR (DMSO d6 , 400 MHz) δ 8.6 (s, 1H);
8.7 (s, 1H);8.7 (s, 1H);
11,8 - 14,7 (breit, 2H).11.8 - 14.7 (broad, 2H).
Beispiel 3Example 3
Verfahren zur Herstellung von 4-Hydroxypyrimidin-5-carbonsäureamid Zu einer Natriummehtylat Lösung (55,88 g, 0,30 mol, 29%> in Methanol) fügte man bei Raumtemperatur Malonsäurediamid (10,75 g, 0,10 mol) zu und verdünnte mit Tetrahydrofuran. Man gab bei Raumtemperatur das gemass Beispiel 1 hergestellte Goldreagenz (18,0 g, 0,11 mol) zu und leitete während 24 Stunden Argon durch, um das freiwerdende Dimethylamin auszutreiben. Der pH- Wert wurde dann mit einer wässrigen Salzsäurelösung auf 7,4 eingestellt und das Tetrahydrofuran am Rotationsverdampfer weitgehend entfernt. Die erhaltene Suspension wurde mit aq. HC1 auf pH = 5,5 gestellt und auf Rückflusstemperatur erhitzt. Man fügte nochmals Wasser zu, um alles in Lösung zu bringen, dann gab man Aktivkohle zu liess weitere 15 min unter Rückfluss rühren. Nach langsamem Abkühlen auf Raumtemperatur fielen leicht gelbe Kristalle aus, die nach Filtration unter Vakuum bei 40°C getrocknet wurden. Man erhielt das Titelprodukt in einer Ausbeute von 5,58 g (80 %).Process for the preparation of 4-hydroxypyrimidine-5-carboxamide: To a sodium methylate solution (55.88 g, 0.30 mol, 29%> in methanol), malonic acid diamide (10.75 g, 0.10 mol) was added at room temperature and diluted with tetrahydrofuran. The gold reagent prepared according to Example 1 (18.0 g, 0.11 mol) was added at room temperature and argon was bubbled through for 24 hours in order to drive off the dimethylamine released. The pH was then adjusted to 7.4 with an aqueous hydrochloric acid solution and the tetrahydrofuran was largely removed on a rotary evaporator. The suspension obtained was adjusted to pH = 5.5 with aq. HC1 and heated to reflux temperature. Water was added again to make everything in solution bring, then activated carbon was allowed to stir under reflux for a further 15 min. After slowly cooling to room temperature, slightly yellow crystals precipitated out, which were dried after filtration under vacuum at 40 ° C. The title product was obtained in a yield of 5.58 g (80%).
1H NMR (DMSOd6, 400 MHz) δ = 7,7 (s, breit, 1H);1H NMR (DMSO d6 , 400 MHz) δ = 7.7 (s, broad, 1H);
8.4 (s, 1H);8.4 (s, 1H);
8.5 - 8,6 (s, breit, 1H);8.5 - 8.6 (s, broad, 1H);
8.6 (s, 1H).8.6 (s, 1H).
Beispiel 4Example 4
Verfahren zur Herstellung von 5-CyanpyrimidinolProcess for the preparation of 5-cyanopyrimidinol
Zum vorgelegten Natriummethylat (54,02 g, 0,30 mol, 29% in Methanol) gab manTo the initially introduced sodium methylate (54.02 g, 0.30 mol, 29% in methanol) was added
Cyanacetamid (8,58 g, 0,10 mol) Man fügte 150 ml Dimethoxyethan zu. Dann gab man das feste, gemass Beispiel 1 hergestellte Goldreagenz (18,08 g, 0,11 mol) spatelweise zu. Man liess die Suspension über Nacht bei Raumtemeperatur rühren. Die gelbe Suspension wurde auf eine wässrige, eiskalte Salzsäurelösung (2 eq. HC1) gegossen und auf pH 5,5 gestellt. Nach Abdampfen der org. Lösungsmittel fiel das Produkt aus der Wasserphase aus. Durch Digerieren in Wasser und anschliessender Filtration konnte man das Titelprodukt in einer Ausbeute von: 9,14 g (75%) in Form eines gelben Feststoffs erhalten.Cyanoacetamide (8.58 g, 0.10 mol) 150 ml of dimethoxyethane were added. Then the solid gold reagent prepared according to Example 1 (18.08 g, 0.11 mol) was added in spatulas. The suspension was allowed to stir overnight at room temperature. The yellow suspension was poured onto an aqueous, ice-cold hydrochloric acid solution (2 eq. HC1) and adjusted to pH 5.5. After evaporating the org. The product precipitated out of solvent from the water phase. By digesting in water and subsequent filtration, the title product could be obtained in a yield of: 9.14 g (75%) in the form of a yellow solid.
1H NMR (DMSOd6, 400 MHz) δ = 8,2 (s, 1H); 8,3 (s, 1H). 1H NMR (DMSO d6 , 400 MHz) δ = 8.2 (s, 1H); 8.3 (s, 1H).
oO
Beispiel 5Example 5
Verfahren zur Herstellung von 5-Cyan-4-pyrimidin-thiolProcess for the preparation of 5-cyan-4-pyrimidine thiol
Zum vorgelegten Natriummethylat (24,3 g, 0,135 mol, 29% in Methanol) fügte man bei Raumtemperatur 2-Cyan-thioacetamid (4,5 g, 0,045 mol). Man fügte 100 ml Dimethoxyethan zu. Anschliessend gab man das gemass Beispiel 1 hergestellte2-Cyano-thioacetamide (4.5 g, 0.045 mol) was added at room temperature to the sodium methylate (24.3 g, 0.135 mol, 29% in methanol). 100 ml of dimethoxyethane were added. The product prepared in accordance with Example 1 was then added
Goldreagenz ( 8,1g, 0,050 mol) zu und liess das Reaktionsgemisch ca. 5 Stunden bei Raumtemperatur rühren. Man erhitzte kurz auf 50 °C und liess über Nacht bei Raumtemperatur stehen. Das Dimethoxyethan wurde am Rotationsverdampfer abgezogen, 20 ml Wasser wurden zugefügt, dann wurde das Reaktionsgemisch im Eisbad abgekühlt. Mit 30 ml 2N aq HCl-Lösung wurde der pH auf 5,5 eingestellt. Nach erneutem Abkühlen wurde der ausgefallene Feststoff abfiltriert, mit wenig kaltem Wasser nachgewaschen und bei 40 °C im Vakuumtrockenschrank getrocknet. Man erhielt so das Titelprodukt in einer Ausbeute von 5,57 g (90,4%) in Form eines orangen Feststoffes.Gold reagent (8.1 g, 0.050 mol) and the reaction mixture was stirred for about 5 hours at room temperature. The mixture was heated briefly to 50 ° C. and left to stand at room temperature overnight. The dimethoxyethane was removed on a rotary evaporator, 20 ml of water were added, then the reaction mixture was cooled in an ice bath. The pH was adjusted to 5.5 with 30 ml of 2N aq HCl solution. After cooling again, the precipitated solid was filtered off, washed with a little cold water and dried at 40 ° C. in a vacuum drying cabinet. The title product was thus obtained in the form of an orange solid in a yield of 5.57 g (90.4%).
Η NMR (DMSOd6, 400 MHz) δ = 8,42 (s, 1H);Η NMR (DMSO d6 , 400 MHz) δ = 8.42 (s, 1H);
8,48 (s, 1H). 8.48 (s, 1H).

Claims

Patentansprüche: Claims:
1. Verfahren zur Herstellung von substituierten Pyrimidinderivaten der allgemeinen Formel1. Process for the preparation of substituted pyrimidine derivatives of the general formula
worin Y ein Sauerstoffatom oder ein Schwefelatom bedeutet und R für Cyano oder für eine Gruppewherein Y represents an oxygen atom or a sulfur atom and R represents cyano or a group
worin R flir gegebenenfalls substituiertes Alkyl, Alkoxy, Hydroxy, Amino, Alkylamino, Dialkylamino, Phenyl, Benzyl steht, dadurch gekennzeichnet, dass man ein [3-(Dimethylamino)-2-azaprop-2-en-l-yliden] dimethylammonium halogenid der allgemeinen Formelwherein R stands for optionally substituted alkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, phenyl, benzyl, characterized in that one of a [3- (dimethylamino) -2-azaprop-2-en-l-ylidene] dimethylammonium halide general formula
XX
worin X ein Halogenatom bedeutet mit einer Verbindung der allgemeinen Formelwherein X represents a halogen atom with a compound of the general formula
YY
H2N A^R inH 2 NA ^ R in
worin Y und R die genannte Bedeutung hat in Gegenwart einer Base zur Umsetzung bringt. wherein Y and R has the meaning given in the presence of a base for reaction.
2. Verfahren nach Patentanspruch 1, dadurch gekennzeichnet, dass als Verbindung der allgemeinen Formel II [3-(Dimethylamino)-2-azaprop-2-en-l-yliden] dimethylammonium chlorid verwendet wird.2. The method according to claim 1, characterized in that chloride is used as the compound of the general formula II [3- (dimethylamino) -2-azaprop-2-en-l-ylidene] dimethylammonium.
3. Verfahren nach Patentanspruch 1 oder 2, dadurch gekennzeichnet, dass als Base ein Alkalialkoholat eingesetzt wird.3. The method according to claim 1 or 2, characterized in that an alkali metal alcoholate is used as the base.
4. Verfahren nach einem der Patentansprüche 1 bis 3, dadurch gekennzeichnet, dass die Umsetzung in Gegenwart eines Lösungsmittels bei einer Temperatur zwischen 20°C und 100°C durchgeführt wird.4. The method according to any one of claims 1 to 3, characterized in that the reaction is carried out in the presence of a solvent at a temperature between 20 ° C and 100 ° C.
5. Verfahren zur Herstellung von substituierten Pyrimidinderivaten der allgemeinen Formel5. Process for the preparation of substituted pyrimidine derivatives of the general formula
worin Y ein Sauerstoffatom oder ein Schwefelatom bedeutet und R flir Cyano oder flir eine Gruppe wherein Y represents an oxygen atom or a sulfur atom and R for cyano or for a group
worin R für gegebenenfalls substituiertes Alkyl, Alkoxy, Hydroxy, Amino,wherein R represents optionally substituted alkyl, alkoxy, hydroxy, amino,
Alkylamino, Dialkylamino, Phenyl oder Benzyl steht, dadurch gekennzeichnet, dass in der ersten Stufe ein Cyanurhalogenid mit N,N-Dimethylformamid in ein [3- (Dimethylamino)-2-azaprop-2-en-l -yliden] dimethylammonmmhalogenid der allgemeinen FormelAlkylamino, dialkylamino, phenyl or benzyl, characterized in that in the first stage a cyanuric halide with N, N-dimethylformamide in a [3- (dimethylamino) -2-azaprop-2-en-1-ylidene] dimethylammonmmhalide of the general formula
X ^N^N^N^ II worin X ein Halogenatom bedeutet überführt wird und darauf in der zweiten Stufe mit einer Verbindung der allgemeinen FormelX ^ N ^ N ^ N ^ II wherein X is a halogen atom is transferred and then in the second stage with a compound of the general formula
YY
,R III, R III
H2NH 2 N
worin Y und R die genannte Bedeutung haben in Gegenwart einer Base zur Umsetzung gebracht wird.wherein Y and R have the meaning given is reacted in the presence of a base.
6. Verfahren nach Patentanspruch 5, dadurch gekennzeichnet, dass als Verbindung der allgemeinen Formel II [3-(Dimethylamino)-2-azaprop-2-en-l-yliden] dimethylammonium chlorid verwendet wird.6. The method according to claim 5, characterized in that chloride is used as the compound of the general formula II [3- (dimethylamino) -2-azaprop-2-en-l-ylidene] dimethylammonium.
7. Verfahren nach Patentanspruch 5, dadurch gekennzeichnet, dass die Umsetzung in der ersten Stufe mit Cyanurchlorid durchgeführt wird.7. The method according to claim 5, characterized in that the reaction in the first stage is carried out with cyanuric chloride.
8. Verfahren nach einem der Patentansprüche 5 bis 7, dadurch gekennzeichnet, dass als Base ein Alkalialkoholat eingesetzt wird.8. The method according to any one of claims 5 to 7, characterized in that an alkali metal alcoholate is used as the base.
9. Verfahren nach einem der Patentansprüche 5 bis 8, dadurch gekennzeichnet, dass die Umsetzung in der zweiten Stufe in Gegenwart eines Lösungsmittels bei einer9. The method according to any one of claims 5 to 8, characterized in that the reaction in the second stage in the presence of a solvent at a
Temperatur zwischen 20°C und 100°C durchgeführt wird.Temperature between 20 ° C and 100 ° C is carried out.
10. Verfahren nach einem der Patentansprüche 5 bis 9 dadurch gekennzeichnet, dass das aus der ersten Stufe resultierende [3-(Dimethylamino)-2-azaprop-2-en-l-yliden] dimethylammoniumhalogenid nicht isoliert wird. 10. The method according to any one of claims 5 to 9, characterized in that the resulting from the first stage [3- (dimethylamino) -2-azaprop-2-en-l-ylidene] dimethylammonium halide is not isolated.
EP98901950A 1997-01-13 1998-01-08 Process for preparing substituted pyrimidine derivatives Expired - Lifetime EP0964855B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH5597 1997-01-13
CH5597 1997-01-13
PCT/EP1998/000074 WO1998030549A1 (en) 1997-01-13 1998-01-08 Process for preparing substituted pyrimidine derivatives

Publications (2)

Publication Number Publication Date
EP0964855A1 true EP0964855A1 (en) 1999-12-22
EP0964855B1 EP0964855B1 (en) 2001-10-17

Family

ID=4178290

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98901950A Expired - Lifetime EP0964855B1 (en) 1997-01-13 1998-01-08 Process for preparing substituted pyrimidine derivatives

Country Status (11)

Country Link
US (1) US6114527A (en)
EP (1) EP0964855B1 (en)
JP (1) JP4143740B2 (en)
AT (1) ATE207062T1 (en)
AU (1) AU5862398A (en)
CA (1) CA2275400C (en)
DE (1) DE59801768D1 (en)
DK (1) DK0964855T3 (en)
ES (1) ES2165668T3 (en)
PT (1) PT964855E (en)
WO (1) WO1998030549A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ20013691A3 (en) * 1999-04-15 2002-04-17 Basf Aktiengesellschaft Process for preparing substituted pyrimidines
US6281358B1 (en) 1999-04-15 2001-08-28 American Cyanamid Company Process for the preparation of substituted pyrimidines
US8299035B2 (en) 2008-05-15 2012-10-30 Taisho Pharmaceutucal Co., Ltd. 10a-azalide compound having 4-membered ring structure
TW201821400A (en) * 2016-10-19 2018-06-16 日商旭硝子股份有限公司 Method for manufacturing nitrogen-containing compound

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1806867C3 (en) * 1968-11-04 1974-07-18 Byk-Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz Process for the preparation of substituted 4-hydroxy pyrimidines
DE3811621A1 (en) * 1988-04-07 1989-10-26 Merck Patent Gmbh METHOD FOR PRODUCING 1H-IMIDAZOLE-5-CARBONIC ACID ESTERS OR NITRILES AND PYRROL-3,4-CARBONIC ACID ESTERS OR NITRILES AND USE OF THE PRODUCED COMPOUNDS FOR SYNTHESISING PILOCARPINE

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9830549A1 *

Also Published As

Publication number Publication date
DK0964855T3 (en) 2001-11-19
JP4143740B2 (en) 2008-09-03
EP0964855B1 (en) 2001-10-17
JP2001508058A (en) 2001-06-19
ES2165668T3 (en) 2002-03-16
CA2275400A1 (en) 1998-07-16
PT964855E (en) 2002-04-29
WO1998030549A1 (en) 1998-07-16
ATE207062T1 (en) 2001-11-15
US6114527A (en) 2000-09-05
AU5862398A (en) 1998-08-03
CA2275400C (en) 2008-07-15
DE59801768D1 (en) 2001-11-22

Similar Documents

Publication Publication Date Title
JP4525625B2 (en) Process for producing 2,5-diamino-4,6 dichloropyrimidine
JP6511346B2 (en) Method of synthesizing halogenated cyclic compound
DE69723846T2 (en) Process for the preparation of sildenafil
JP2012255028A (en) Method for producing hydantoin derivative
JP2008526936A (en) New method for producing substituted indoles
EP0964855B1 (en) Process for preparing substituted pyrimidine derivatives
DE69816080T2 (en) METHOD FOR PRODUCING CHINOLINE DERIVATIVES
EP0552758B1 (en) N-5-protected 2,5-diamino-4,6-dichloropyrimidines and process for their preparation
DE69817868T2 (en) 4-FLUORO-3-OXOCARBONIC ACID ESTERS AND THEIR PRODUCTION
EP0798297B1 (en) Process for the preparation of 2-alkoxy-6-(trifluoromethyl)-pyrimidine-4-ol
DE69928454T2 (en) Pyridazinone derivatives useful as intermediates for herbicides
DD285349A5 (en) METHOD FOR PRODUCING SUBSTITUTED PYRIDYL ALKYL KETONES
EP1023272B1 (en) Process for preparing alkoxytriazolinones
EP0889038B1 (en) Process for the preparation of alkoxy-or aryloxypyrazine derivatives
EP0547411A1 (en) Process for the preparation of 2-substituted 4,6-dialkoxypyrimidines
EP3368510A1 (en) Method for synthesizing 2-alkyl-4-trifluoromethyl-3-alkylsulfonylbenzoic acids
DE60111834T2 (en) PROCESS FOR THE PREPARATION OF 3-AMINO-1,5-BENZODIAZEPINE DERIVATIVES
JPH0859630A (en) Production of quinazoline-2,4-dione
JP2002535311A (en) Synthesis of 3-amino-2-chloro-4-methylpyridine from malononitrile and acetone
JP3085513B2 (en) Method for producing 5-chloro-4-hydroxy-6-methylpyrimidine
JP3832980B2 (en) A novel intermediate for the production of tetrahydrofuranyl derivatives with insecticidal activity
EP0345464A2 (en) Process for the preparation of substituted 3-amino-2-(benzoyl)acrylic acid esters as well as a process for the preparation of intermediates for antibacterial active agents from these compounds
EP0491328B1 (en) Process for the preparation of piperazinyl-pyrimidin derivatives
CH685497A5 (en) Prepn. of 2-substd.-4,6-di:hydroxy-pyrimidine derivs.
DE19507915A1 (en) Process for the preparation of pyrazoles

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19990429

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB IE IT LI NL PT SE

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

17Q First examination report despatched

Effective date: 20000718

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: LONZA AG

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FI FR GB IE IT LI NL PT SE

REF Corresponds to:

Ref document number: 207062

Country of ref document: AT

Date of ref document: 20011115

Kind code of ref document: T

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: GERMAN

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REF Corresponds to:

Ref document number: 59801768

Country of ref document: DE

Date of ref document: 20011122

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)

Effective date: 20020118

ET Fr: translation filed
REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2165668

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20020110

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20101112

Year of fee payment: 14

Ref country code: IE

Payment date: 20101111

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20101111

Year of fee payment: 14

Ref country code: FI

Payment date: 20101112

Year of fee payment: 14

Ref country code: CH

Payment date: 20101215

Year of fee payment: 14

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20090108

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20101112

Year of fee payment: 14

Ref country code: SE

Payment date: 20101115

Year of fee payment: 14

Ref country code: BE

Payment date: 20101112

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20101112

Year of fee payment: 14

Ref country code: DE

Payment date: 20101116

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20110120

Year of fee payment: 14

Ref country code: IT

Payment date: 20110119

Year of fee payment: 14

PGRI Patent reinstated in contracting state [announced from national office to epo]

Ref country code: IT

Effective date: 20110616

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20111128

Year of fee payment: 15

Ref country code: DK

Payment date: 20111122

Year of fee payment: 15

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20120709

BERE Be: lapsed

Owner name: *LONZA A.G.

Effective date: 20120131

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20120801

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20120108

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120108

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120109

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120801

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120108

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120131

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120131

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 59801768

Country of ref document: DE

Effective date: 20120801

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120709

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120108

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 207062

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120108

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120131

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120801

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120108

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120108

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20130705

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120109

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20130930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130131

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130131